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A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges

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Advances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper
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  STUDY PROTOCOL Open Access A nationwide study on reproductive function,ovarian reserve, and risk of prematuremenopause in female survivors of childhoodcancer: design and methodological challenges Annelies Overbeek  1,2 † , Marleen H van den Berg 1* † , Leontien CM Kremer 3 , Marry M van den Heuvel-Eibrink  4 ,Wim JE Tissing 5 , Jacqueline J Loonen 6 , Birgitta Versluys 7 , Dorine Bresters 8 , Gertjan JL Kaspers 1 , Cornelis B Lambalk  2 ,Flora E van Leeuwen 9 and Eline van Dulmen-den Broeder 1 on behalf of the DCOG LATER-VEVO study group Abstract Background:  Advances in childhood cancer treatment over the past decades have significantly improved survival,resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affectreproductive function. This paper describes the design and encountered methodological challenges of anationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarianreserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOGLATER-VEVO study. Methods:  The study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical,menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonalanalyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-yearsurvivors of childhood cancer treated in the Netherlands, whereas the control group consists of age-matchedsisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participatein both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges wereencountered involving the study population: dealing with bias due to the differences in characteristics of severaltypes of (non-) participants and finding an adequately sized and well-matched control group. Moreover, thechallenges related to the data collection process included: differences in response rates between web-based andpaper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of womenusing hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements. Discussion:  The DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning toconduct large cohort studies on late effects may encounter similar challenges as those encountered during thisstudy. The solutions to these challenges described in this paper may be useful to these investigators. Trial registration:  NTR2922; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922 Keywords:  Childhood cancer survivors, Adverse effects, Female fertility, Study design, Methodological challenges * Correspondence: † Equal contributors 1 Department of Paediatrics, Division of Paediatric Oncology/Haematology,VU University Medical Center, PO Box 7057, Amsterdam 1007MB, The NetherlandsFull list of author information is available at the end of the article © 2012 Overbeek et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the srcinal work is properly cited. Overbeek   et al. BMC Cancer   2012,  12 :363http://www.biomedcentral.com/1471-2407/12/363  Background Cancer treatment can have detrimental effects on repro-ductive function. In women, there is evidence that bothchemo- and radiotherapy can adversely affect ovarianfunction, ovarian reserve and uterine function, clinically leading to sub- or infertility, premature menopause and/or adverse pregnancy outcomes [1-9]. However, previousstudies addressing the late effects of cancer treatment onfemale fertility have several limitations. Clinical ovarianreserve tests are often lacking (i.e. data from question-naires only) [1-6,10-19], and study populations are oftensmall and heterogeneous [20-27]. Therefore, we designedthe DCOG LATER-VEVO study (Dutch Childhood On-cology Group - Long term Effects after ChildhoodCancer/ Fertility, Ovarian reserve and Premature Meno-pause (Dutch acronym)) in the Netherlands. Patient in-clusion started in 2008.The study aims to evaluate the effects of cancer treat-ment on the reproductive system of female childhoodcancer survivors (CCS) in the Netherlands and their riskof premature menopause. The effects of treatment ingeneral will be assessed, as well as the effects of differenttreatment modalities, doses of drugs, radiation sites anddoses, and age at time of treatment. The study includesa questionnaire survey and a full panel of ovarian func-tion and reserve tests. The DCOG LATER-VEVO study is the first nationwide childhood cancer survivor study in the Netherlands and during the study period severalmethodological challenges were encountered.In this paper the key methodological and practicalchallenges are discussed as well as the way they wereaddressed. Other investigators planning to conduct largenationwide cohort studies among childhood cancer sur- vivors will benefit from this information when faced withsimilar challenges. Patients and methods Design and study population The DCOG LATER-VEVO study is a multi-center retro-spective cohort study including female 5-year survivorsof childhood cancer. The study consists of three parts: aquestionnaire survey, the provision of a blood sample,and a transvaginal ultrasound measurement of the re-productive organs, the latter two requiring a visit to theoutpatient clinic. Approval was obtained from the rele- vant medical ethics committees and written informedconsent was obtained from all participants.Eligible cohort members are selected from a cohort of patients treated for childhood cancer between 1963 and2002 at one of the seven Dutch paediatric oncology -and stem cell transplant centers, collectively known asthe Dutch Childhood Oncology Group - LongtermEffects after Childhood Cancer (DCOG LATER). Thisgroup has developed a nationwide electronic databaseincluding patient and treatment details of all CCS in theNetherlands (DCOG LATER database). The study popu-lation consists of those female CCS who were treated fora malignancy or central nervous system tumour beforethe age of 18, who survived for at least 5 years afterdiagnosis, and who were at least 18 years at study entry (n=2331). The exclusion criteria for participation in thestudy include: deceased before the start of the study (n=271), living abroad or unknown address (n=75), notbeing able to speak or read Dutch (n=1), having severemental sequelae (n=40), being treated for second malig-nant neoplasm at the time of study inclusion (n=34),and previously having indicated not willing to participatein research (n=13). Thus, a total of 1897 female child-hood cancer survivors are eligible for participation inthe DCOG LATER-VEVO study.Sisters of participating CCS who have never been diag-nosed with cancer, who are able to read and speakDutch, and who are 18 years or older, are asked to par-ticipate in the control group of the study. For this pur-pose participating CCS are asked to contact all sistersmeeting the inclusion criteria and to provide their con-tact information to the investigators. If a female survivorchooses to not register one or more available sisters, thereason is enquired about. Approach of study participants and data collection All eligible women receive a mailed package containingextensive study information, an informed consent andrefusal form, and a questionnaire. They are asked tocomplete the questionnaire and return it with a signedinformed consent form. Furthermore, they are asked toindicate on the informed consent form in which partsof the study they are willing to participate. In case of noresponse within 3 weeks, postal reminders are sent.When again after 3 weeks no response has beenreceived, the women are contacted by telephone.Women who are not willing to participate in either partof the study are asked to complete a refusal form onwhich they can indicate the reason for not wanting toparticipate. These non-participants are asked to com-plete a brief questionnaire regarding parity, wish to havechildren, subfertility, subfertility treatment, and educa-tional level in order to adjust for possible bias. The enve-lope containing the study information package is sealedand put in another envelop, together with a cover letterin which the study is explained very briefly. This is donein order to give the survivors the opportunity to choosewhether or not they want to be confronted with theextensive study information. If not, they can send theunopened package return to sender. Figure 1 depictsthe various response categories that apply to the DCOGLATER-VEVO study. Overbeek   et al. BMC Cancer   2012,  12 :363 Page 2 of 11http://www.biomedcentral.com/1471-2407/12/363  The data collected for survivors and siblings are thesame, with the exception of data related to the anti-cancertreatment in the past. For both survivors and siblings in-formation on reproductive and medical history is obtainedby a questionnaire which is available either as hard copy or online. This questionnaire is an adaptation of a well-tested questionnaire used by the Department of Epidemi-ology of the Netherlands Cancer Institute in a large-scaleDutch cohort study of long-term effects of ovarianstimulation for in vitro fertilization [28,29]. It addressesthe following issues: socio-demographic characteristics,menstrual history, desire to have children, reproductivehistory, pregnancy information, pregnancy outcomes,details of offspring, menopausal symptoms and meno-pause, use and duration of use of exogenous hormones,use and duration of use of fertility drugs and assisted re-productive techniques, family history of cancer and sub-/infertility, co-morbidities, and life style behaviour.In order to assess reproductive function and ovarianreserve a blood sample is drawn and a transvaginal ultra-sound of the reproductive organs is performed. From theblood sample, FSH, LH, estradiol, inhibin-B, prolactin,and AMH concentrations are determined as well as theFSH receptor genotype. The ultrasound measurements,which assess the number of antral follicles in both ovar-ies as well as the length and width of the ovaries and theuterus, are performed by specifically trained personnelusing a HD11 XE ultrasound system with a transvaginalprobe which can perform three-dimensional (3D)imaging (EnVisor HD, Philips Medical Systems, Eindho- ven, the Netherlands). First, a 2D ultrasound assessmentof the pelvis is performed after which an automatedmechanical sweep produces the 3D data. An ultrasoundmeasurement is not performed when the participantindicates in the questionnaire that she has not yet beeninvolved in sexual intercourse, unless she explicitly states Figure 1  Response flow chart.  The following categories and definitions are used to classify participants and non-participants in the DCOGLATER-VEVO study: 1)  “ eligible subjects ”  are individuals registered in the DCOG LATER database who were confirmed as meeting the studyeligibility criteria; 2)  “ participants ”  are those who consented to participate; 3)  “ non-participants ”  are individuals who declined participation verballyor in writing, who returned the envelope with study information unopened or who, at first indicated they were willing to participate butultimately did not do so; 4) subjects are considered  “ lost to follow-up ”  if they were not located after intensive tracing efforts; and 5) individualsare classified as  “ pending ”  when they are actively being traced and recruited to participate. Overbeek   et al. BMC Cancer   2012,  12 :363 Page 3 of 11http://www.biomedcentral.com/1471-2407/12/363  she wants to undergo an ultrasound. Both the bloodsampling and ultrasound measurements require specifictiming. For both CCS and controls not using hormonalcontraceptives this timing is as follows: (1) on day 2 – 5 of a natural menstrual cycle; (2) on any convenient momentin case of amenorrhea (no menses>6 months). In thosewho are using hormonal contraceptives, alternativemethods of timing were used (see section  “ The valueof hormonal and ultrasound markers while using oralcontraceptives ” ).Since January 2008, invitations have been sent to 1611female CCS and 429 sister controls from all participatingcenters and data collection is still ongoing. As of March1 st 2012, 1215 CCS and 333 sister controls haveresponded, whereas from the remaining 396 survivorsand 96 controls no response has been received to date.Table 1 describes the response and participation rates of CCS and controls as of March 1 st 2012. Challenges The challenges encountered during the study can bedivided into two categories: challenges related to thestudy population and challenges related to the data col-lection procedures. Study population Bias due to different characteristics of the women inthe various response groups Eligible study subjects can either respond (responders)or not respond to the study invitation (non-responders).The responders either decide to participate (participants)or not to participate in the study (non-participants). Whenthey decide to participate they can subsequently chooseto take part in one, two or all three parts of the study.In total, three groups of participants are distinguished:1. questionnaire only; 2. questionnaire and blood sample;3. questionnaire, blood sample and transvaginal ultra-sound. The responders may not be comparable to thenon-responders and the same is true for non-participants versus participants. In addition, subjects who choose tocomplete the questionnaire only may not be comparableto those who also participate in the clinical assessment.This may potentially lead to selection bias, which may influence the validity of the study results. Therefore, it isimportant to identify potential differences between the various response groups in order to be able to control forselection bias during the data analyses of the DCOGLATER-VEVO study.In order to identify the presence and direction of possible selection bias interim data analyses were per-formed, in which differences between the characteristicsof responders and non-responders were compared.Results showed that the age at study invitation (28.8 vs.28.2 years), age at diagnosis (6.96 vs. 7.06 years) andtime since treatment (7998 vs. 7658 days) were not dif-ferent between responders and non-responders. Inaddition, differences between the characteristics of parti-cipants and non-participants were compared. Resultsshowed that the non-participating CCS (n=274) did notsignificantly differ from the participating CCS regardingcurrent age (p=0.09). In addition, there were no signifi-cant differences in age at diagnosis or in time since diag-nosis (p=0.23 and p=0.24, respectively). Of the 274non-participants, 17% (n=46) were willing to completethe brief non-participant questionnaire. Data from thisquestionnaire showed no significant differences withregard to educational level, although the proportion of women with a high educational level in the participantsgroup was substantially higher compared to the non-participants group (39.9% vs. 26.1%, p=0.09). Moreover,a larger proportion of the non-participants reported toalready have offspring in comparison with participants.However, this difference was not significant either(46.3% vs. 33.9%, p=0.10). Nevertheless, this may sug-gest that women with proven fertility may be less likely to participate in the study than those who have not givenbirth (yet). This implies that caution should be takenwhen interpreting the results of the DCOG LATER-VEVO study since an overestimation of the adverseeffects of the cancer treatment on reproductive out-comes (i.e. actual fertility) might be introduced. Werealize, however, that the number of women completingthe non-participant questionnaire was rather low. Asa consequence, this group of women may not be fully representative of the total group of non-participants.However, the non-participants that did and thosewho did not complete the non-participant questionnaireappeared not to significantly differ regarding currentage, age at diagnosis, and time since diagnosis. Table 1 Response and participation rates of childhoodcancer survivors and sister controls in the DCOGLATER-VEVO study* Survivors sistercontrolsInvited  1611 429Response received (responders) 1215 (75%) 333 (78%)No response received (non-responders) 396 (25%) 96 (22%) RespondersParticipants Questionnaire only 306 (19%) 96 (22%)Questionnaire and blood sample 126 (8%) 43 (10%)Questionnaire, blood sample andtransvaginal ultrasound509 (32%) 174 (41%) Non-participants  274 (17%) 20 (5%) * Rates acquired as of March 1 st  2012 . Overbeek   et al. BMC Cancer   2012,  12 :363 Page 4 of 11http://www.biomedcentral.com/1471-2407/12/363  With regard to possible selection bias within the par-ticipating groups, we evaluated the differences in charac-teristics between those participating in the questionnairepart only and those participating in both the question-naire and the clinical part (blood and/or ultrasound) of the study (Table 2). It appeared that women who com-pleted the questionnaire only were older, had a longerfollow-up time since diagnosis, were less likely to behighly educated, were more likely to have had inter-course and to have offspring than women who alsoagreed to participate in the clinical part. Participants who ultimately did not show up for outpatient clinic visit  If participants decide to provide a blood sample and/orundergo a transvaginal ultrasound, they are asked tocontact the research staff on a specific day of their men-strual cycle in order to plan the clinical assessment atthe outpatient clinic. However, we experienced thatsome participants who initially consented to a clinicalassessment did not (yet) follow-up on their decision6 months after their written consent (n=90) . Twenty-seven women (30%) have expressed a reason (pregnancy,breastfeeding, illness or disability, and personal or family responsibilities) while the remaining 63 have not yetcontacted the research staff, even after several remin-ders. Ultimately, these women will be classified as non-participants to the clinical part of the study. Finding an adequately sized and well-matched control group Sisters of participating CCS are invited as controls, sincethey have the same genetic and socio-economic back-ground (which might influence fertility and other out-comes). However, the inclusion of only sisters in thecontrol group has shown to result in insufficientnumbers compared to the number of CCS (941 versus313, see also Table 1). The reason is two-fold: not allparticipating CCS have an eligible sister aged 18 years orolder and not all CCS with eligible sisters gave permis-sion to contact their sisters for the control group. Forthe DCOG LATER-VEVO study this may ultimately re-sult in insufficient power for certain subgroup analyses.Moreover, not all research questions of the study requirea control group that is genetically and/or socioeconomi-cally comparable to the survivor group. Therefore, itwas decided to expand the control group by includingwomen from the general population as well.For this purpose, general practitioners of the partici-pating CCS are asked to randomly select and invite sub- jects from their female patient population. For logisticalreasons, we selected general practitioners practiceslocated in the area surrounding the coordinating center.In order to ensure a comparable age distributionbetween CCS and controls, these general practitionersare asked to select women within a specified age rangeof five years (so-called  “ GP controls ” ). For these women,the same inclusion criteria apply as for the sister con-trols: never to have been diagnosed with cancer, able toread and speak Dutch, and 18 years or older. Thismethod of approach resulted in 1184 women who wereinvited to participate in the DCOG LATER-VEVO study as controls. So far, 935 (79%) have responded and 429women have consented to participate, 308 of whom inthe clinical part of the study.Within the group of eligible controls recruited via thegeneral practitioners, we conducted a non-responderanalysis. A random sample (n=200) was drawn from theGP controls who did not respond to the study invitation.From these women the following variables were col-lected from the medical records at the general practi-tioner ’ s office: age, having offspring, maternal age at first Table 2 Comparison of several characteristics between two different groups of participants Variable Participants P valueParticipating in questionnairepart only (n=306)Participating in questionnaireand clinical part (n=635)Age (years)  30 (18 – 52) 27 (18 – 56) <0.001 Age at diagnosis (years)  6 (0 – 16) 6 (0 – 17) NS Time since diagnosis (days)  8280.5 (2563 – 15423) 7418 (2068 – 14612) 0.001 High education (n/N) (%)*  103/300 (34.3) 267/619 (43.1) 0.002 In committed relationship (n/N) (%)*  217/304 (71.4) 431/633 (68.1) NS Has had intercourse (n/N) (%)*  248/303 (81.8) 555/631 (88.0) 0.01 Has offspring (n/N) (%)*  146/304 (48.0) 183/633 (28.9) <0.001 Has previously consulted a gynaecologistfor fertility problems (n/N) (%)* 46/289 (15.9) 72/621 (11.6) NS Data presented as median (range) unless indicated otherwise. NS=not significant. * Total N does not correspond with the number mentioned in the heading of thetable because of missing data. Overbeek   et al. BMC Cancer   2012,  12 :363 Page 5 of 11http://www.biomedcentral.com/1471-2407/12/363
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